To date ten different genes have been identified that are associated with inherited predisposition to metastatic disease, with evidence in both mouse model tumor systems and human patient populations. Unexpected, due to the complexity of the metastatic process, further analysis into the mechanistic basis of these genes has revealed that many of them appear to be functioning within a single molecular pathway. Due to the complexity of the metastatic cascade, which requires many different interactions and steps, it was anticipated that little overlap between mechanisms would be observed for most of the genes. The repeated association of the metastasis susceptibility genes with this single molecular pathway suggests that it may play a major role in the metastatic process in breast cancer. It is hoped that further characterization and investigation into the pathway may lead to greater insights into the underlying processes associated with metastatic disease. However, despite the convergence on this molecular pathway, evidence from our laboratory suggests that there must be additional pathways for tumor dissemination and metastasis. Human association studies interrogating the role of our metastasis susceptibility genes in breast cancer has demonstrated an association only in patients diagnosed without tumor cells in their sentinel lymph nodes. Patients who had tumor cells within the sentinel lymph nodes at diagnosis of the primary tumor showed no association between variants in the metastasis susceptibility genes and disease outcome. This result suggests that there must be at least two different genetically defined mechanisms for breast cancer metastasis that need to be investigated to fully understand tumor dissemination and metastasis. In addition to studying the intrinsic factors associated with metastasis, we have been investigating the effects of various environmental exposures on metastatic disease. In collaboration with investigators at UNC and NCSU we have demonstrated that high fat diet significantly increases the probability of developing metastatic disease. The increase in metastatic disease can be ascribed to changes in gene expression and cellular biology of not only the tumor cells themselves, but are also probably due to changes in non-tumor tissues induced by high fat diets. Furthermore, in collaboration other NIH investigators we have investigated the effect of specific cancer treatment regimens on metastatic spread and found some evidence that this specific treatment may in some cases promote tumor metastasis.